Abstract
Besides treating acute flares, the management of SLE should aim at preventing organ damage accrual and drug-associated harms, improving health-related quality of life and prolonging ...survival. At present, therapy is based on combinations of antimalarials (mainly HCQ), considered the backbone of SLE treatment, glucocorticoids and immunosuppressive drugs. However, these regimens are not universally effective and a substantial degree of damage can be caused by exposure to glucocorticoids. In this review we provide a critical appraisal of the efficacy and safety of available treatments as well as a brief discussion of potentially novel compounds in patients with SLE. We emphasize the use of methylprednisolone pulses for moderate–severe flares, followed by low–moderate doses of oral prednisone with quick tapering to maintenance doses of ≤5 mg/day, as well as the prompt institution of immunosuppressive drugs in the setting of severe disease but also as steroid-sparing agents. Indications for the use of biologic agents, namely belimumab and rituximab, in refractory or organ-threatening disease are also presented. We conclude by proposing evidence- and experience-based treatment strategies tailored to the clinical scenario and prevailing organ involvement that can aid clinicians in managing this complex disease.
Summary The antiphospholipid syndrome causes venous, arterial, and small-vessel thrombosis; pregnancy loss; and preterm delivery for patients with severe pre-eclampsia or placental insufficiency. ...Other clinical manifestations are cardiac valvular disease, renal thrombotic microangiopathy, thrombocytopenia, haemolytic anaemia, and cognitive impairment. Antiphospholipid antibodies promote activation of endothelial cells, monocytes, and platelets; and overproduction of tissue factor and thromboxane A2. Complement activation might have a central pathogenetic role. Of the different antiphospholipid antibodies, lupus anticoagulant is the strongest predictor of features related to antiphospholipid syndrome. Therapy of thrombosis is based on long-term oral anticoagulation and patients with arterial events should be treated aggressively. Primary thromboprophylaxis is recommended in patients with systemic lupus erythematosus and probably in purely obstetric antiphospholipid syndrome. Obstetric care is based on combined medical-obstetric high-risk management and treatment with aspirin and heparin. Hydroxychloroquine is a potential additional treatment for this syndrome. Possible future therapies for non-pregnant patients with antiphospholipid syndrome are statins, rituximab, and new anticoagulant drugs.
Objective
To analyze the influence of 2 different treatment strategies on general and specific damage accrual in patients with systemic lupus erythematosus (SLE).
Methods
Two cohorts were identified ...according to the responsible physicians: patients treated at the autoimmune diseases unit (ADU), and patients treated by other members of the internal medicine (IM) department. Members of the ADU worked with a protocol including the universal prescription of hydroxychloroquine (HCQ), the use of maximum oral prednisone dosages ≤30 mg/day and maintenance therapy with ≤5 mg/day, by using methylprednisolone pulses and/or early immunosuppressive (IS) drugs. We analyzed the influence of these 2 treatment strategies on damage accrual, both general and domain specific, attributed to glucocorticoids, cardiovascular (CV) disease, SLE, and unclassified, since the diagnosis of disease in patients with a followup ≥5 years.
Results
A total of 74 patients were included in the ADU group and 213 in the IM group. They were comparable for most demographic and lupus‐related variables. ADU patients received prednisone later and at lower doses, more methylprednisolone pulses, earlier IS drugs and more HCQ (P < 0.05 for all comparisons). The Systemic Lupus Erythematosus Disease Activity Index score decreased similarly in both cohorts (P = 0.4). Patients in the ADU group were less likely to accrue any damage (P = 0.007). They accrued less glucocorticoid‐related (adjusted hazard ratio HR 0.23 95% confidence interval (95% CI) 0.07–0.80), CV disease (adjusted HR 0.28 95% CI 0.08–0.95), and unclassified damage (adjusted HR 0.58 95% CI 0.3–1.1). Both groups accrued similar SLE‐related damage (adjusted HR 0.84 95% CI 0.40–1.75).
Conclusion
The use of reduced oral prednisone doses, which was possible by combining different therapies, reduced glucocorticoid‐related damage and improved CV prognosis without increasing damage caused by SLE.
Video Video
Objective
The objective of this study was to analyze the effect of methylprednisolone pulses (MP), given during the first year after the diagnosis of systemic lupus erythematosus (SLE), in achieving ...prolonged remission according to the degree of lupus activity at presentation.
Methods
We conducted an observational study of routine clinical care data from the Lupus‐Cruces‐Bordeaux cohort. The end point was prolonged remission (ie, during five consecutive yearly visits). The effect of MP on remission during the first year was analyzed in the whole cohort and according to the baseline Systemic Lupus Erythematosus Disease Activity Index 2000 score: <6, 6 to 12, and >12, reflecting mild, moderate, and severe activity, respectively. For adjustment, logistic regression with propensity score (PS) and other therapeutic covariates was performed.
Results
Two hundred thirty‐three patients were included. Prolonged remission was achieved by 132 patients (57%). MP were associated with prolonged remission (PS‐adjusted odds ratio OR 2.50, 95% confidence interval CI 1.04–623, P = 0.042). A strong clinical effect was seen among patients with moderate (adjusted OR 5.28, 95% CI 1.27–21.97, P = 0.022) and moderate‐severe SLE activity (adjusted OR 4.07, 95% CI 1.11–14.82, P = 0.033). The administration of MP resulted in reduced average dosages of prednisone during the first year among patient with moderate (mean 6.6 vs 10.2 mg/day, P = 0.017) and severe activity (mean 14 vs 28 mg/day, P = 0.015). The odds of prolonged remission were increased by longer‐term use of hydroxychloroquine (HCQ) and decreased by higher initial doses of prednisone.
Conclusion
This study supports the use of MP to induce prolonged remission in patients with SLE, particularly in those with moderate and severe activity. The extended use of HCQ also contributes to achieve prolonged remission.
The objective was to develop evidence-based recommendations for the management of antiphospholipid syndrome (APS) in adults. Based on evidence from a systematic literature review and expert opinion, ...overarching principles and recommendations were formulated and voted. High-risk antiphospholipid antibody (aPL) profile is associated with greater risk for thrombotic and obstetric APS. Risk modification includes screening for and management of cardiovascular and venous thrombosis risk factors, patient education about treatment adherence, and lifestyle counselling. Low-dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with systemic lupus erythematosus without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles. Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists (VKA) with a target international normalised ratio (INR) of 2-3. In patients with APS with first arterial thrombosis, treatment with VKA with INR 2-3 or INR 3-4 is recommended, considering the individual's bleeding/thrombosis risk. Rivaroxaban should not be used in patients with APS with triple aPL positivity. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3-4 or switch to low molecular weight heparin may be considered. In women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended. In patients with recurrent pregnancy complications, increase of heparin to therapeutic dose, addition of hydroxychloroquine or addition of low-dose prednisolone in the first trimester may be considered. These recommendations aim to guide treatment in adults with APS. High-quality evidence is limited, indicating a need for more research.
To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).
This ...international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects.
The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria.
These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research.
A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a ...systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibility with pregnancy and lactation was found for antimalarials, sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity. Insufficient documentation in regard to fetal safety implies the discontinuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use apply for the few proven teratogenic drugs and the large proportion of medications for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemination of the data to health professionals and patients as well as their implementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease.
Glucocorticoids (GC) have long been one of the cornerstones of the treatment of systemic lupus erythematosus (SLE). However, it is now a well-established fact that GC are a major cause of ...irreversible damage.1 Therefore, strategies to decrease GC load without compromising the adequate control of disease activity are essential in the management of SLE. Hydroxychloroquine (HCQ) should be considered the main GC-sparing drug in lupus. Its continued use has been associated to a myriad of beneficial effects, including the prevention of damage accrual and the improvement of survival, but also to a better control of lupus activity and, thus, a reduced need for GC use. Also, immunosuppressive drugs such as cyclophosphamide, azathioprine and methotrexate, have been extensively used throughout different clinical scenarios in order to decrease GC doses.2 Although clinical trials with this group of drugs are few, their use has long been validated by clinical practice. More recently, biologic agents approved for SLE such as belimumab and anifrolumab have also been shown to allow a good control of disease activity whilst reducing the dose of GCs.3 4 However, it is my view that the best GC-sparing drugs are…GCs. Pulses of methyl-prednisolone (MP), 125–500 mg/d, given for short periods of time (usually 3 days) have been shown to be the most effective way of rapidly controlling lupus flares through the activation of the non-genomic pathway.5 6 Therefore, the use of MP in the induction of remission, not only in life-threatening scenarios, combination therapy with HCQ and immunosuppressive drugs and a rapid tapering with a slow withdrawal of prednisone is our proposal for the successful management of SLE. In cases in which this scheme fails to adequately control lupus activity, the addition of biologic drugs should be considered. Ugarte-Gil MF, et al. Impact of glucocorticoids on the incidence of lupus-related major organ damage: a systematic literature review and meta-regression analysis of longitudinal observational studies. Lupus Sci Med. 2021 Dec;8(1):e000590. doi: 10.1136/lupus-2021-000590. Pego-Reigosa JM, et al. Efficacy and safety of nonbiologic immunosuppressants in the treatment of nonrenal systemic lupus erythematosus: a systematic review. Arthritis Care Res. (Hoboken). 2013 Nov;65(11):1775–85. doi: 10.1002/acr.22035. Touma Z, et al. Belimumab use, clinical outcomes and glucocorticoid reduction in patients with systemic lupus erythematosus receiving belimumab in clinical practice settings: results from the OBSErve Canada Study. Rheumatol Int. 2017 Jun;37(6):865–873. doi: 10.1007/s00296-017-3682-9. Epub 2017 Mar 9. Bruce IN, et al. Sustained glucocorticoid tapering in the phase 3 trials of anifrolumab: a post hoc analysis of the TULIP-1 and TULIP-2 trials. Rheumatology (Oxford). 2023 Apr 3;62(4):1526–1534. doi: 10.1093/rheumatology/keac491. Ruiz-Irastorza G, et al. Prolonged remission in SLE is possible by using reduced doses of prednisone: an observational study from the lupus-cruces and lupus-bordeaux inception cohorts. Autoimmun Rev. 2019 Sep;18(9):102359. doi: 10.1016/j.autrev.2019.102359. Epub 2019 Jul 16. Ruiz-Irastorza G, Bertsias G. Treating systemic lupus erythematosus in the 21st century: new drugs and new perspectives on old drugs. Rheumatology (Oxford). 2020 Dec 5;59(Suppl5):v69-v81. doi: 10.1093/rheumatology/keaa403. Learning Objectives Describe the concept and the need for sparing GC Describe different drugs used to treat SLE with a GC-sparing effect Discuss results from recent studies on the efficacy and toxicity of therapeutic schemes using methyl-prednisolone pulses followed by lower doses of prednisone in active lupus Describe practical guidelines for using glucocorticoid-sparing drugs in the different settings of active lupus
Objective
To analyze whether changes in serum 25‐hydroxyvitamin D (25OHD) levels affect activity, irreversible organ damage, and fatigue in systemic lupus erythematosus (SLE).
Methods
We performed an ...observational study of 80 patients with SLE included in a previous cross‐sectional study of 25(OH)D, reassessed 2 years later. Oral vitamin D3 was recommended in those with low baseline 25(OH)D levels. The relationship between changes in 25(OH)D levels from baseline and changes in fatigue (measured by a 0–10 visual analog scale VAS), SLE activity (measured by the Systemic Lupus Erythematosus Disease Activity Index SLEDAI), and irreversible organ damage (measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index SDI) were analyzed.
Results
Sixty patients took vitamin D3. Mean 25(OH)D levels increased among all treated patients (P = 0.044), in those with baseline vitamin D levels <30 ng/ml (P < 0.001), and in those with baseline vitamin D levels <10 ng/ml (P = 0.005). Fifty‐seven patients (71%) still had 25(OH)D levels <30 ng/ml and 5 (6%) had 25(OH)D levels <10 ng/ml. Inverse significant correlations between 25(OH)D levels and the VAS (P = 0.001) and between changes in 25(OH)D levels and changes in the VAS in patients with baseline 25(OH)D levels <30 ng/ml (P = 0.017) were found. No significant correlations were seen between the variation of the SLEDAI or SDI values and the variation in 25(OH)D levels (P = 0.87 and P = 0.63, respectively).
Conclusion
Increasing 25(OH)D levels may have a beneficial effect on fatigue. Our results do not support any effects of increasing 25(OH)D levels on SLE severity, although they are limited by the insufficient 25(OH)D response to the recommended regimen of oral vitamin D3 replacement.
To determine nephritis outcomes in a prospective multi-ethnic/racial SLE inception cohort.
Patients in the Systemic Lupus International Collaborating Clinics inception cohort (≤15 months of SLE ...diagnosis) were assessed annually for estimated glomerular filtration rate (eGFR), proteinuria and end-stage renal disease (ESRD). Health-related quality of life was measured by the Short Form (36 questions) health survey questionnaire (SF-36) subscales, mental and physical component summary scores.
There were 1827 patients, 89% females, mean (s.d.) age 35.1 (13.3) years. The mean (s.d.) SLE duration at enrolment was 0.5 (0.3) years and follow-up 4.6 (3.4) years. LN occurred in 700 (38.3%) patients: 566/700 (80.9%) at enrolment and 134/700 (19.1%) during follow-up. Patients with nephritis were younger, more frequently men and of African, Asian and Hispanic race/ethnicity. The estimated overall 10-year incidence of ESRD was 4.3% (95% CI: 2.8%, 5.8%), and with nephritis was 10.1% (95% CI: 6.6%, 13.6%). Patients with nephritis had a higher risk of death (HR = 2.98, 95% CI: 1.48, 5.99; P = 0.002) and those with eGFR <30 ml/min at diagnosis had lower SF-36 physical component summary scores (P < 0.01) and lower Physical function, Physical role and Bodily pain scores. Over time, patients with abnormal eGFR and proteinuria had lower SF-36 mental component summary (P ≤ 0.02) scores compared to patients with normal values.
LN occurred in 38.3% of SLE patients, frequently as the initial presentation, in a large multi-ethnic inception cohort. Despite current standard of care, nephritis was associated with ESRD and death, and renal insufficiency was linked to lower health-related quality of life. Further advances are required for the optimal treatment of LN.
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